Abstract
Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.
Original language | English |
---|---|
Pages (from-to) | 1125-1132 |
Number of pages | 8 |
Journal | Nature Genetics |
Volume | 54 |
Issue number | 8 |
Early online date | 14 Jul 2022 |
DOIs | |
Publication status | Published - Aug 2022 |
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In: Nature Genetics, Vol. 54, No. 8, 08.2022, p. 1125-1132.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways
AU - 23andMe Research Team
AU - Watanabe, Kyoko
AU - Jansen, Philip R.
AU - Savage, Jeanne E.
AU - Nandakumar, Priyanka
AU - Wang, Xin
AU - Agee, Michelle
AU - Aslibekyan, Stella
AU - Auton, Adam
AU - Bell, Robert K.
AU - Bryc, Katarzyna
AU - Clark, Sarah K.
AU - Elson, Sarah L.
AU - Fletez-Brant, Kipper
AU - Fontanillas, Pierre
AU - Furlotte, Nicholas A.
AU - Gandhi, Pooja M.
AU - Heilbron, Karl
AU - Hicks, Barry
AU - Huber, Karen E.
AU - Jewett, Ethan M.
AU - Jiang, Yunxuan
AU - Kleinman, Aaron
AU - Lin, Keng Han
AU - Litterman, Nadia K.
AU - McCreight, Jennifer C.
AU - McIntyre, Matthew H.
AU - McManus, Kimberly F.
AU - Mountain, Joanna L.
AU - Mozaffari, Sahar V.
AU - Noblin, Elizabeth S.
AU - Northover, Carrie A.M.
AU - O’Connell, Jared
AU - Pitts, Steven J.
AU - Poznik, G. David
AU - Sathirapongsasuti, J. Fah
AU - Shelton, Janie F.
AU - Shi, Jing
AU - Shringarpure, Suyash
AU - Tian, Chao
AU - Tung, Joyce Y.
AU - Tunney, Robert J.
AU - Vacic, Vladimir
AU - Wang, Wei
AU - Hinds, David A.
AU - Gelernter, Joel
AU - Levey, Daniel F.
AU - Polimanti, Renato
AU - Van Someren, Eus J.W.
AU - Smit, August B.
AU - Posthuma, Danielle
AU - Stein, Murray B.
N1 - Funding Information: We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. Funding Information: We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/8
Y1 - 2022/8
N2 - Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.
AB - Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.
UR - http://www.scopus.com/inward/record.url?scp=85134384334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85134384334&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41588-022-01124-w
DO - https://doi.org/10.1038/s41588-022-01124-w
M3 - Article
C2 - 35835914
SN - 1061-4036
VL - 54
SP - 1125
EP - 1132
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -